Pearl of the Month

Hareen Seerha; Douglas S. Paauw, MD

DISCLOSURES | February 28, 2025

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A 50-year-old White woman presents for evaluation of a new skin lesion on her face that has been present for the past 4 months. Biopsy reveals a squamous cell carcinoma (SCC). She previously had an SCC removed from her left arm 2 years ago. She is currently taking lisinopril, amlodipine, hydrochlorothiazide, omeprazole, turmeric, and sertraline.

Which medication would it be appropriate to replace? 
    A) Lisinopril
    B) Amlodipine
    C) Hydrochlorothiazide
    D) Omeprazole
    E) Sertraline

We think replacing her hydrochlorothiazide would be appropriate, given that she has developed two SCCs at a young age.

Thiazides

As we continue to prescribe thiazides for hypertensive patients, it may be worthwhile to initiate and discuss skin protection alongside treatment. The photosensitizing properties of thiazide diuretics have raised concerns that these treatments may increase the risk for skin cancer.Douglas S. Paauw, MD

A meta-analysis conducted by Shin and colleagues analyzed nine observational studies to investigate the association between thiazide use and skin cancer. Thiazide use was significantly associated with small SCCs with an adjusted odds ratio (AOR) of 1.86 (95% CI, 1.23-2.80). Thiazide use had marginally increased associations with basal cell carcinoma (BCC) (AOR, 1.19; 95% CI, 1.02-1.38) and malignant melanoma (AOR, 1.14; 95% CI, 1.01-1.29). 

Pedersen and colleagues studied a Danish database and found that high use of hydrochlorothiazide (> 50,000 mg) was associated with ORs of 1.29 (95% CI, 1.23-1.35) for BCC and 3.98 (95% CI, 3.68-4.31) for SCC. They found that there was a dose-response effect; the highest cumulative dose category (> 200,000 mg hydrochlorothiazide) had ORs of 1.54 (95% CI, 1.38-1.71) for BCC and 7.38 (95% CI, 6.32-8.60) for SCC.

Rahamimov and associates  looked at the risk in kidney transplant patients of developing skin cancer on thiazide diuretic treatment. As we know, immunosuppression increases the risk of developing cancer in general; however, there is concern that this risk will increase with a concurrent thiazide prescription. Rahamimov’s group conducted a retrospective analysis of 520 kidney transplant recipients on immunosuppressants and thiazides in 2010-2015. Exposure to thiazides 3 years after transplant was associated with an increased risk for skin cancer (P =.004), particularly nonmelanoma skin cancer.Hareen Seerha 

Rahamimov’s group suggests establishing dermatology care for kidney transplant patients receiving thiazide treatments in areas with high ultraviolet light. It is also important to assess skin malignancy risk factors, do thorough skin exams before and while prescribing thiazides to patients, and educate patients about ultraviolet light protection. This is especially important for patients with light complexions, as there did not appear to be an increased risk in a large study of an Asian population in Taiwan. 

It makes sense to avoid thiazide diuretics, if possible, in the highest-risk patients — those with multiple previous skin cancers and those who are chronically immunosuppressed. 

ACE Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors have been revolutionary for patients with cardiovascular disease; however, recent studies have raised concerns over whether this mortality-reducing drug increases the risk for lung cancer. 

A study published by the American Heart Association used a nested case-control design to assess lung cancer associated with ACE inhibitor use compared with angiotensin II receptor blocker (ARB) use. The researchers conducted a population-wide study using Danish national and administrative registries from 2000 to 2015. They found that while low cumulative ACE inhibitor doses showed neutral associations with lung cancer, high cumulative doses were associated with increased odds of lung cancer. 

A meta-analysis conducted by Wu and colleagues analyzed records from 11 studies to assess the association between ACE inhibitor use and lung cancer. The researchers accounted for factors such as smoking, race, and age. They concluded that ACE inhibitors are a relevant factor in lung carcinogenesis and pose a higher risk compared with ARBs, especially among Asian populations. Another study within this meta-analysis showed that statins may mitigate this association, reducing the risk when a statin and an ACE inhibitor are prescribed together. 

In recent years, there has been increasing evidence supporting the connection between ACE inhibitors and the development of lung cancer. ACE inhibitors result in the accumulation of bradykinin and substance P. Not only does this often cause a notorious cough, but these inflammation markers are associated with tumor proliferation and angiogenesis. However, more randomized controlled trials are needed to determine the causal association between ACE inhibitors and lung cancer. ARBs, although currently second-line drugs, do not cause accumulation of bradykinin. Perhaps it is time to rethink our approach to cardiovascular disease treatments.

Pearls

• Considering the risk that thiazides and ACE inhibitors can pose for developing malignancies, it is important to screen patients for risk factors prior to prescribing treatment.
• Although skin exams can be tedious and patients may push back on sunscreen use, these conversations may be important for those taking thiazides; avoidance of thiazides in high-risk patients may be warranted.
• Perhaps it is time to consider ARBs over ACE inhibitors.

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